Development of a Pediatric Mylelodysplastic Syndrome Patient Registry

儿童骨髓增生异常综合征（pMDS）是一种罕见的造血系统疾病，其特征是异质性疾病，包括原发性或新生MDS，以及先天性或获得性骨髓衰竭（BMF）综合征或细胞毒性治疗后的“继发性MDS”。迄今为止，对导致经前综合症的起始事件知之甚少，因此没有针对性的治疗方法；骨髓移植是这些患者唯一的治疗选择。临床和实验室表现的异质性使得研究pMDS和识别新的遗传改变变得困难。迄今为止，对儿童期MDS启动事件的有限了解阻碍了具有生物学相关性的分子分类。因此，这种疾病主要是根据形态学和细胞遗传学标准来分类的。与老年MDS不同，某些遗传条件，如遗传性骨髓衰竭综合征，以及获得性再生障碍性贫血和MDS的一级亲属易使年轻患者患MDS。这可能为pMDS发病机制的独特特征提供重要的见解。为了能够系统地研究该疾病，需要大量具有临床病史和辅助信息（如细胞遗传学）的样本。到目前为止，在美国还没有这么大的样本收集。因此，我们寻求建立一个pMDS患者登记和组织库，这将使我们能够收集足够的患者资料，以便将来对这一疾病家族进行系统和深入的分析。患者登记将提供一个平台，通过标准化的形态学、细胞遗传学和分子分析来提高MDS儿童的诊断准确性（例如，我们寻求利用登记来执行全基因组筛选方法，以识别与pMDS有关的新基因）。它还将使我们能够评估pMDS不同亚型的频率，以及评估移植后的生存率、复发率、发病率和死亡率。我们已经开始与Charlotte Niemeyer博士领导的欧洲MDS工作组（eogg -MDS）进行讨论，以学习他们在欧洲建立类似登记处的经验，该登记处目前已经存在了10年。总之，我们寻求在美国建立一个儿童MDS患者登记处，这不仅将通过使用标准化的方法提高诊断，而且还将使我们和其他未来的合作者能够对一种通常难以收集足够数量的患者样本进行分析的罕见疾病进行有意义的转化研究。最终的希望是，来自患者登记的发现将为pMDS的发病机制和潜在的分子事件提供新的和重要的见解，这可能导致未来疾病特异性治疗的应用。这个项目将由博士领导。David A. Williams（以其在造血干细胞和骨髓衰竭疾病方面的专业知识而闻名）和Mark D. Fleming（儿科血液病理学专家）合作努力，利用他们在血液学和骨髓衰竭疾病方面的临床专业知识以及他们在儿科血液病理学方面的专业知识。Drs。威廉姆斯和弗莱明将由Inga Hofmann Zhang博士加入该项目，她在儿科血液学/肿瘤学和血液病理学方面的培训和背景将为执行该项目提供额外的技能。该项目将在波士顿儿童医院进行，该医院在儿科护理、研究和转化医学创新方面处于全国领先地位。波士顿儿童医院有很大的转诊基数，并与其他中心有良好的联系。这将允许我们扩展推荐基础，以更快地填充此注册表。此外，儿童医院在临床血液学和血液学方面已经拥有完善的基础设施，这将有助于实施这一建议。在挑战基金的帮助下，我们有信心凭借我们在造血和血液病理学领域的独特专业知识，我们有能力建立一个成功的儿科MDS患者登记。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (07) Enhancing Clinical Trials and specific Challenge Topic 07-DK-103: Support for Registries Pediatric myelodysplastic syndrome (pMDS) is a rare hematopoietic disease characterized by a heterogeneous group of disorders that include primary or de novo MDS, and "secondary MDS" following congenital or acquired bone marrow failure (BMF) syndromes or cytotoxic therapy. To date, very little is known about the initiating events leading to pMDS, and thus no targeted therapies exist; bone marrow transplantation is the only therapeutic option for these patients. The heterogeneity in the clinical and laboratory presentation has made it difficult to study pMDS and to identify novel genetic alterations. Limited knowledge of initiating events in childhood MDS have to date prevented a molecular classification with biological relevance. Therefore the disease remains largely classified by morphological and cytogenetic criteria. Unlike MDS in the elderly, certain genetic conditions such as inherited bone marrow failure syndromes, as well as acquired aplastic anemia and MDS in a first-degree relative predispose young patients to MDS. This may provide important insights into the unique features of the pathogenesis of pMDS. In order to be able to study the disease systematically, a large number of samples that are well annotated with a clinical history and ancillary information such as cytogenetics are needed. To date such a large sample collection does not exist within the USA. Therefore, we seek to build a pMDS patient registry and tissue repository that will allow us to gather sufficient patient material to permit systematic and in depth analysis of this family of disorders in the future. A patient registry will provide a platform to improve accuracy of diagnosis for children with MDS by standardized review of morphology and cytogenetics and molecular analysis (for example we seek to utilize the registry to perform whole genome-wide screening approach to identify novel genes involved in pMDS). It will also allow us to evaluate the frequency of the different subtypes of pMDS, as well as assessing survival, relapse rate, morbidity and mortality after HSCT. We have already initiated discussions with the European Working Group of MDS (EWOG-MDS), led by Dr. Charlotte Niemeyer, to learn from their experience setting up a similar registry in Europe that has now been in existence for 10 years. Taken together, we seek to establish a pediatric MDS patient registry in the US that will not only improve the diagnosis by using a standardized approach, but it will also allow us and other future collaborators to perform meaningful translational research on a rare disease for which it is often difficult to collect sufficient numbers of patient samples for analysis. The ultimate hope is that the findings that will emerge from the patient registry will provide new and important insights into the pathogenesis and underlying molecular events that play a role in pMDS, which might lead to future disease-specific therapeutic applications. This project will be lead by Drs. David A. Williams (known for his expertise in hematopoietic stem cells and bone marrow failure disorders) and Mark D. Fleming, (an expert Pediatric Hematopathologist) in collaborative effort, utilizing both their clinical expertise in hematology and marrow failure disorders as well as their expertise in pediatric hematopathology. Drs. Williams and Fleming will be joined in this project by Dr. Inga Hofmann Zhang whose training and background in Pediatric Hematology/Oncology and Hematopathology will provide additional skills to execute the project. This project will be carried out at Children's Hospital Boston, a national leader in pediatric care, and innovation in research and translational medicine. Children's Hospital Boston has a large referral base and is well connected with other centers. This will permit us to expand the referral base to more quickly populate this registry. Furthermore Children's Hospital already has a well-developed infrastructure in clinical Hematology and Hematopathology that will facilitate the execution of this proposal. With the help of funds available through the challenge grants we are confident that with our unique expertise in the fields of hematopoiesis and hematopathology we are well equipped to establish a successful Pediatric MDS patient registry. PUBLIC HEALTH RELEVANCE: Pediatric myelodysplastic syndrome (pMDS) is a rare hematopoietic disease characterized by a heterogeneous group of disorders. To date very little is known about the initiating events leading to pMDS, and thus no targeted therapies exist; bone marrow transplantation is the only therapeutic option for these patients. Our objective is to establish a patient registry and tissue bank that will permit us to reach our overall goal to define the genetics of childhood MDS and identify pathways for therapy, and ultimately translate this knowledge to improve the outcome for these children.